CN104055792A - Application of cydiodine to treatment of otitis media - Google Patents
Application of cydiodine to treatment of otitis media Download PDFInfo
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- CN104055792A CN104055792A CN201410327951.XA CN201410327951A CN104055792A CN 104055792 A CN104055792 A CN 104055792A CN 201410327951 A CN201410327951 A CN 201410327951A CN 104055792 A CN104055792 A CN 104055792A
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Abstract
The invention relates to an application of cydiodine to treatment of otitis media and particularly provides a solid pharmaceutical composition used to be dropped into ears. The solid pharmaceutical composition comprises cydiodine and a diluent, wherein the diluent is selected from glucose, mannitol, sorbitol, lactose, fructose, sodium chloride, saccharose and the like and a combination thereof. The invention also provides an application of the solid pharmaceutical composition to prevention and treatment of inflammatory diseases of ears, and a medicine box product comprising a packaging box, the solid pharmaceutical composition packaged in the packaging box and a solvent for dissolving the solid pharmaceutical composition. The solid pharmaceutical composition provided by the invention has an excellent effect for treating otitis media.
Description
Technical field
The invention belongs to medical technical field, relate to the purposes of cydiodine treatment otitis media.The present invention also provides a kind of pharmaceutical composition that is used for the treatment of otitis media, wherein comprises cydiodine.Use present composition treatment otitis media to there is good effect.
Background technology
Known iodine molecule is halogenation bacterium protein directly, without selectively killing various microorganisms, comprises bacterial propagule, fungus, brood cell etc.
Existing many Operands are for clinical, povidone iodine and preparation thereof that for example Chinese Pharmacopoeia version in 2010 is recorded, this povidone iodine is the complex of polyvinylpyrrolidone and iodine, is 9～12% containing available iodine, and it has emulsifiable paste, bolt, solution, gel as the main dosage form of Cidex-7.
Again for example, the Cydiodine buccal tablet that Chinese Pharmacopoeia version in 2010 is recorded, it is as a kind of Cidex-7, and active component is the molecular iodine of cyclodextrin parcel, and every amount of iodine is 1.5mg.In vitro tests proves, in the time that cydiodine available iodine concentration is 10ppm, acts on and can kill aerobe in 2 minutes: escherichia coli, staphylococcus aureus, beta hemolytic streptococcus; To peptostreptococcus anaerobius, 10ppm effect can all be killed for 8 minutes, when 25ppm, acts on 8 minutes, can effectively kill and not understand sugared bacteroid and actinomyces pseudonecrophorus; When 120ppm, act on 30 minutes, all kill Bacillus anthracoides brood cell; When 50ppm, fungus is had to bacteriostasis.Clinical results shows that the sterilization anti-infectious function of Dobell is reliable, and has convergence, eliminates myxedema, analgesic effect is fast, removing oral cavity stink, Dobell can promote the functions such as oral ulcer mucosa healing, for oral cavity, throat local application, to oral mucosa nonirritant.Clinically for chronic pharyngolaryngitis, candida albicans infection stomatitis, oral ulcer, chronic gingivitis, periodontal disease and erosive lichen planus etc.
Otitis media is the inflammation of middle ear mucosa of tympanic cavity.How to infect and to cause by antibacterial.The traditional Chinese medical science claims this sick for " otopyosis ", " chronic suppurative otitis media ", thinks because of prevailing the causing of dampness-heat in the liver and gallbladder (fire) pathogen.Otitis media is the inflammatory lesion of involving all or part of structure of middle ear (comprising pharyngotympanic tube, tympanum, tympanic antrum and mastoid air cell), is apt to occur in child.Can be divided into apyetous and suppurative two large classes.Apyetous person comprises secretory otitis media, barotraumatic otits media etc., and suppurative person has acute and chronic dividing.Specificity inflammation is shown in very little, as tuberculous otitis media etc.
The cause of disease of otitis media mainly contains following 6 aspects: (1) acute otitis media is the acute suppurative inflammation of middle-ear mucosa, is infected by pharyngotympanic tube approach.After flu, inflammation pharyngeal, nose spreads to pharyngotympanic tube, and congested, swelling appear in pharyngeal opening of auditory tube and tube chamber mucosa, and ciliary movement generation obstacle, causes otitis media.Common pathogenic bacterium are mainly streptococcus pneumoniae, hemophilus influenza etc.(2) in nasal mucus, contain a large amount of virus and antibacterial, if nostril, both sides all pinches firmly and blows, pressure forces nasal mucus to be extruded to choana, arrives pharyngotympanic tube, causes otitis media.(3) while swimming, should avoid water to swallow in entrance, cause otitis media in order to avoid water enters middle ear by nasopharynx part.The perforation of ear drum due to wound, forbids dripping any water sample liquid, in order to avoid affect the healing of wound.Available sterilized cotton ball stops up external auditory meatus, in order to avoid infection-induced otitis media.(4) if infant dorsal position is sucked the breast, because child's pharyngotympanic tube is more straight, and tube chamber is shorter, and internal diameter is wider, and milk can be choked and cause otitis media into middle ear through pharyngotympanic tube.(5) smoking comprises passive smoking, also can cause otitis media.Smoking can cause the arteriosclerosis of general, and especially the nicotine in medicated cigarette enters blood, makes small blood vessel spasm, and blood viscosity increases, and hardens to the arteriole of internal ear supply blood, causes internal ear blood supply insufficiency, has a strong impact on audition.(6) long-time music of listening the large decibel of rock and roll class with earphone, if the time is longer, also easily causes chronic otitis media.
The clinical manifestation of otitis media mainly contains following aspect:
1, suppurative otitis media
(1) acute suppurative otitis media: infected the otitis media causing by suppurative bacterium, its symptom is mainly otalgia, suppurates.Children's's General Symptoms is more obvious than adult, can have heating, vomiting etc.Serious complication has intracranial complication, as meningitis, brain abscess etc.Other complication have labyrinthitis, facial paralysis etc.
(2) chronic suppurative otitis media: refer to middle-ear mucosa, periosteum or deeply reach the chronic suppurative inflammation of sclerotin.Primary disease is comparatively common clinically, is often interrupted or persistence is suppurated, the perforation of ear drum, auditory dysesthesia be as main clinical manifestation taking in ear, when serious, can cause the complication outside intracranial, cranium.1. General Symptoms: weight differs.Can be afraid of cold, heating, weak, loss of appetite.Children's's General Symptoms is heavier, the symptoms of digestive tract such as normal companion vomiting, diarrhoea.Once tympanum perforation, body temperature decline gradually, and General Symptoms obviously alleviates.2. otalgia: ear deep pain, increases the weight of gradually.As pulsation jumping pain or twinge, can be to homonymy head or tooth radiation.When swallowing and coughing, otalgia increases the weight of, and violent person is unable to fall asleep night for otalgia, dysphoria.After the perforation of ear drum is suppurated, otalgia is paused and is subtracted.3. discharging ear: be the cardinal symptom of primary disease, can be mucus, glutinous pus or pure purulence.Non-dangerous type is suppurated thinner, odorless.Though dangerous type is suppurated seldom, thicker, mostly is pure purulence, and with foreign odor taste.4. auditory dysesthesia and tinnitus: start to feel ear vexed, the audition that continues is gradually fallen, companion's tinnitus.Otalgia play person deafness can be left in the basket.Some patient can vertigo, and after perforation, deafness alleviates on the contrary.5. deaf: weight differs, because being mostly monaural morbidity, easily out in the cold.Be generally conductive deafness.
2, non-suppurative otitis media, secretory otitis media
(1) auditory dysesthesia: when acute secretory otitis media mostly can decline rear in flu, by air, by plane or dive under water, occur auditory dysesthesia, can have " strengthening from sound " phenomenon.The order of severity of otitis media,secretory,chronic patient's deafness often has fluctuation.When compressing tragus or head position change, audition can make moderate progress, and when middle ear effusion is sticky, audition can not change because of the variation of head position.The many main suits without auditory dysesthesia of child, show as father and mother's call are ignored, absent minded, or require excessive volume while seeing TV.
(2) otalgia: can have slight otalgia when acute secretory otitis media, otitis media,secretory,chronic is many can occur otalgia in the time of secondary infection.
(3) the vexed swollen sense of in ear or inaccessible sense.
(4) tinnitus: generally heavy, can be intermittence, when head movement, yawn or audible and gur gling when blowing the nose.Also can there is in ear flowing water in minority patients with secretory otitis media, but the persistent period is very short, is only about a few hours or 1 day.
(5) otoscopy: acute stage tympanum periphery have radial stria vascularis.Pars tensa membranae tympani caves in, and shows as light cone and shortens, is out of shape or disappear; Manubrium of malleus backward, top displacement; Short process of malleus evagination is obvious.When hydrotympanum, tympanum loses normal gloss, is yellowish, orange red or amber; Chronic person's tympanum milky or dusty blue are opaque.If secretions is serosity, and underfill tympanum, can see through tympanum and see fluid level, be concave upright curved line, see through tympanum and sometimes can see bubble, after pharyngotympanic tube catheterization, bubble increases; If in tympanum, hydrops is many, tympanum evagination, tympanum limited range of motion.
At present the treatment of otitis media is mainly contained to following mode: (1) active treatment upper respiratory tract focus disease, as chronic sinusitis, chronic tonsillitis.(2) Drug therapy: simple type is taking local application as main, available antibiotic aqueous solution or antibiotic and steroid hormones mixed liquor, as 0.25% chloromycetin solution, chloromycetin cortisone liquid, ofloxacin ear drops etc., treatment otitis media and otitis externa etc.(3) local application's points for attention: pus in first washing external auditory meatus and tympanum before medication, available 3% hydrogen peroxide or boric acid water clean, and wipe clean or exhaust pus with suction pump and can drip medicine with swab afterwards.Water preparation when pus amount is many, can use boric acid alcohol when amount is few.(4) big perforation of tympanic membrane affects audition, feasible tympanic membrane repairing or tympanoplasty.
But the antibiotic method of existing use still exists many limitations, for example therapeutic effect is limited.Therefore, a kind of new treatment otopathy that what those skilled in the art still expected provide particularly the new method of otitis media for clinical use, expect that especially this method has good therapeutic effect.
Summary of the invention
The object of the present invention is to provide a kind of new particularly new method of otitis media for the treatment of ear disease, expect that especially this method has good therapeutic effect.The inventor have been surprisingly found that, the ear with medicament of making taking cydiodine as active component has good therapeutic effect to otitis media.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides a kind of solid composite medicament of using for dripping ear, and it comprises cydiodine (being the cyclodextrin clathrate of iodine), diluent.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, wherein said diluent is water-soluble diluent.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, wherein said diluent is water-soluble diluent, is selected from: glucose, mannitol, sorbitol, lactose, fructose, sodium chloride, sucrose etc. and their combination.In one embodiment, described water-soluble diluent is selected from: lactose, mannitol with and combination.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, the amount that wherein comprises cydiodine is counted 5 weight portions with iodine (I), the amount of diluent is 20～200 weight portions (amount of for example diluent is 25～150 weight portions, for example, be 30～100 weight portions).
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, it is during with water dissolution the dilution solution that to make containing the concentration of iodine (I) be 1mg/ml, and this solution has the surface tension of 20～100dyn/cm.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, it is during with water dissolution the dilution solution that to make containing the concentration of iodine (I) be 1mg/ml, and this solution has the surface tension of 30～80dyn/cm.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, it is during with water dissolution the dilution solution that to make containing the concentration of iodine (I) be 1mg/ml, and this solution has the surface tension of 40～70dyn/cm.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, it is the form that is tablet, granule or capsule.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, it is the form that is tablet.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, it is the form that is tablet, this tablet is to prepare in the following manner substantially: make the uniform material of cydiodine and mixing diluents flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in and dispose 12～24 hours with the seal box sealing of ethanol saturated air atmosphere; Then this powder material is squeezed into the tablet of bulk, then gained tablet is broken into granule, dry, be pressed into tablet.The inventor have been surprisingly found that, by this process processing, than in using common process processing, can effectively reduce gained tablet in the surface tension that is dissolved in gained solution after water.And this tablet with low surface tension solution is when for otitis media, unexpectedly shows and there is higher therapeutic effect.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, wherein said ethanol is 30～98% ethanol, for example 40～95% ethanol, for example 50～90% ethanol.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, it is the form that is tablet, and it optionally also comprises optional disintegrating agent, optional binding agent and/or optional lubricant.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, wherein said disintegrating agent can be the disintegrating agent of various tablets well known by persons skilled in the art, such as but not limited to carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, corn starch etc.Owing to expecting to dissolve completely in water in solid composite medicament of the present invention, and at tablet of the present invention in the time that reality is used, can make tablet dispersing and dissolving and needn't worry the problem of not disintegrate of tablet by the mode of external force jolting.Therefore, in one embodiment, solid composite medicament of the present invention for example can not add disintegrating agent in tablet.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, wherein said binding agent can be the binding agent of various tablets well known by persons skilled in the art, such as but not limited to water and aquiferous ethanol (wetting agent when they are also commonly referred to and prepare granule), starch slurry, HPMC aqueous solution, PVP aqueous solution etc.It is preferential making water or aquiferous ethanol prepare granule.The purposes of lubricant in solid composite is well known to a person skilled in the art, can be for example to account for 0～5% of composition total weight conventionally, particularly 0～2% (for the situation that makes water or aquiferous ethanol, its consumption is 0%), the PROCESS FOR TREATMENT that uses pre-tabletting to granulate in view of the present invention, therefore in some embodiments of the present invention, these tablets can not add binding agent.Or these binding agents (for example HPMC, PVP) can add with the form of dry powder.
According to the solid composite medicament of the arbitrary embodiment of first aspect present invention, wherein said lubricant can be the lubricant of various tablets well known by persons skilled in the art, such as but not limited to the PEG of molecular weight 4000～10000, stearic acid, magnesium stearate etc.If needed, preferred lubricant is PEG.The purposes of lubricant in solid composite is well known to a person skilled in the art, for example, can be conventionally to account for 0.2～5% of composition total weight particularly 0.5～2%.
Further, second aspect present invention provides described in the arbitrary embodiment of first aspect present invention solid composite medicament in the purposes for the preparation of prevention and treatment ear diseases associated with inflammation.
According to the purposes of the arbitrary embodiment of second aspect present invention, wherein said ear diseases associated with inflammation is to betide the diseases associated with inflammation that middle ear, internal ear etc. are located.
According to the purposes of the arbitrary embodiment of second aspect present invention, wherein said ear diseases associated with inflammation is otitis media.
According to the purposes of the arbitrary embodiment of second aspect present invention, wherein said otitis media comprises non-suppurative otitis media and suppurative otitis media.
According to the purposes of the arbitrary embodiment of second aspect present invention, wherein said suppurative otitis media comprises acute suppurative otitis media and chronic suppurative otitis media.
According to the purposes of the arbitrary embodiment of second aspect present invention, wherein said ear diseases associated with inflammation is to infect by antibacterial the inflammatory diseases causing.
According to the purposes of the arbitrary embodiment of second aspect present invention, wherein said antibacterial infects and refers to that being selected from following antibacterial infects: staphylococcus aureus, Staphylococcus albus, Staphylococcus citreus, Pseudomonas aeruginosa, escherichia coli, Salmonella typhi, Salmonella paratyphi B, alpha streptococcus, group B streptococcus, Diplococcus pneumoniae, Shigella dysenteriae, Bacillus proteus, klebsiella, aerobacteria, enterobacter agglomerans, enterobacter cloacae, bacillus subtilis.In the time using in test, these antibacterials all obtain (and normally separate and obtain easily) and through qualification from clinical separation; In addition, in the time that the present invention uses, be staphylococcus aureus ATCC26112 and Pseudomonas aeruginosa ATCC10211 for Quality Control bacterial strain.
In view of solid composite medicament of the present invention will use as ear drop, in the time of clinical use, the solvent mixed dissolution of itself and Sq is made to solution, therefore, third aspect present invention provides a kind of medicine box product.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, it comprises packing box, is wrapped in solid composite medicament in this packing box and for dissolving the solvent of this solid composite medicament.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, as described in wherein said solid composite medicament embodiment as arbitrary in first aspect present invention.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solid composite medicament comprises cydiodine (being the cyclodextrin clathrate of iodine), diluent.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, the diluent described in wherein said solid composite medicament is water-soluble diluent.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, diluent described in wherein said solid composite medicament is water-soluble diluent, is selected from: glucose, mannitol, sorbitol, lactose, fructose, sodium chloride, sucrose etc. and their combination.In one embodiment, described water-soluble diluent is selected from: lactose, mannitol with and combination.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, the amount that comprises cydiodine in wherein said solid composite medicament is counted 5 weight portions with iodine (I), the amount of diluent is 20～200 weight portions (amount of for example diluent is 25～150 weight portions, for example, be 30～100 weight portions).
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solid composite medicament is during with water dissolution the dilution solution that to make containing the concentration of iodine (I) be 1mg/ml, and this solution has the surface tension of 20～100dyn/cm.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solid composite medicament is during with water dissolution the dilution solution that to make containing the concentration of iodine (I) be 1mg/ml, and this solution has the surface tension of 30～80dyn/cm.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solid composite medicament is during with water dissolution the dilution solution that to make containing the concentration of iodine (I) be 1mg/ml, and this solution has the surface tension of 40～70dyn/cm.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solid composite medicament is the form that is tablet, granule or capsule.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solid composite medicament is the form that is tablet.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solid composite medicament is the form that is tablet, this tablet is to prepare in the following manner substantially: make the uniform material of cydiodine and mixing diluents flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in and dispose 12～24 hours with the seal box sealing of ethanol saturated air atmosphere; Then this powder material is squeezed into the tablet of bulk, then gained tablet is broken into granule, dry, be pressed into tablet.The inventor have been surprisingly found that, by this process processing, than in using common process processing, can effectively reduce gained tablet in the surface tension that is dissolved in gained solution after water.And this tablet with low surface tension solution is when for otitis media, unexpectedly shows and there is higher therapeutic effect.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said ethanol is 30～98% ethanol, for example 40～95% ethanol, for example 50～90% ethanol.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, in wherein said solid composite medicament, be the form that is tablet, it optionally also comprises optional disintegrating agent, optional binding agent and/or optional lubricant.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said disintegrating agent can be the disintegrating agent of various tablets well known by persons skilled in the art, such as but not limited to carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, corn starch etc.Owing to expecting to dissolve completely in water in solid composite medicament of the present invention, and at tablet of the present invention in the time that reality is used, can make tablet dispersing and dissolving and needn't worry the problem of not disintegrate of tablet by the mode of external force jolting.Therefore, in one embodiment, solid composite medicament of the present invention for example can not add disintegrating agent in tablet.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said binding agent can be the binding agent of various tablets well known by persons skilled in the art, such as but not limited to water and aquiferous ethanol (wetting agent when they are also commonly referred to and prepare granule), starch slurry, HPMC aqueous solution, PVP aqueous solution etc.It is preferential making water or aquiferous ethanol prepare granule.The purposes of lubricant in solid composite is well known to a person skilled in the art, can be for example to account for 0～5% of composition total weight conventionally, particularly 0～2% (for the situation that makes water or aquiferous ethanol, its consumption is 0%), the PROCESS FOR TREATMENT that uses pre-tabletting to granulate in view of the present invention, therefore in some embodiments of the present invention, these tablets can not add binding agent.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said lubricant can be the lubricant of various tablets well known by persons skilled in the art, such as but not limited to the PEG of molecular weight 4000～10000, stearic acid, magnesium stearate etc.If needed, preferred lubricant is PEG.The purposes of lubricant in solid composite is well known to a person skilled in the art, for example, can be conventionally to account for 0.2～5% of composition total weight particularly 0.5～2%.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein said solvent is selected from: water, phosphate buffer, citrate buffer, borate buffer solution, acetate buffer etc.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, the amount of wherein said solvent is, while making described solid composite medicament be dissolved in wherein, iodine (I) concentration in solution reaches the scope of 0.2～5mg/ml, for example reach the scope of 0.5～2.5mg/ml, for example, reach the scope of 0.5～2mg/ml.
According to the medicine box product of the arbitrary embodiment of third aspect present invention, wherein also comprise the operation instructions of this medicine box product.In one embodiment, in described operation instructions, recorded to use before this medicine box product described solid composite medicament has been joined to the operating procedure of dissolving in described solvent.
Fourth aspect present invention provides the particularly method of tablet of solid composite medicament described in the arbitrary embodiment of preparation first aspect present invention, it consists essentially of following steps: make the uniform material of cydiodine and mixing diluents flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in and dispose 12～24 hours with the seal box sealing of ethanol saturated air atmosphere; Then this powder material is squeezed into the tablet of bulk, then gained tablet is broken into granule, dry, be pressed into tablet.
According to the method for fourth aspect present invention, as described in wherein said solid composite medicament embodiment as arbitrary in first aspect present invention.
Arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
Be further described to various aspects of the present invention below.
In following Preparation Example part or experimental example part, as do not mentioned in addition, described cydiodine is as CN1028485C (patent of invention description, patent No. ZL90106682.6) cydiodine that makes under " preparation of (one) cydiodine " in description embodiment mono-, through sodium thiosulfate titration, in every gram of material of this cydiodine of preparation, comprise 165mg available iodine (I), cyclodextrin is beta-schardinger dextrin-.
Essence of the present invention is to find that cydiodine adopts particular combinations of the present invention to present the effect of good treatment otitis media, and this good therapeutic effect unexpectedly can be reached by the surface tension that makes composition solution in scope of the present invention.In addition, have been found that the compositions for the present invention formula, when using conventional preparation technology to be prepared into solid pharmaceutical preparation for example when tablet, its aqueous solution shows the surface tension with >85dyn/cm.And in the time using special process of the present invention, its aqueous solution shows the surface tension with <70dyn/cm.Although the present composition has adopted specific technique to obtain this tablet with low surface tension character, but the tablet that this solid composite medicament is prepared with the conventional method of test as a comparison on material composition is identical (because is finally being dried and removing as the granulation wetting agent of water or aquiferous ethanol), and therefore the good therapeutic effect of the present invention should be owing to this character of compositions low surface tension.Further, in view of the solid composite medicament of the present invention that obtains low surface tension can pass through accomplished in many ways, for example process by the ethanol in the present invention's 50～90% concentration ranges, along with the development of pharmaceutical technology, can expect, other can be realized and make tablet aqueous solution reduce capillary preparation technology can to realize equally the object of the invention., the present composition is not limited to its specific preparation technology.
In addition, no matter be to prepare in which way as the cydiodine of activated feedstock, those skilled in the art openly can expect completely that according to the present invention other alternative that obtains cydiodine also can realize the object of the invention.In the present invention, cydiodine can be referred to as CDI.
Detailed description of the invention
The following examples that provide only for task of explanation instead of for, should not be interpreted as limiting by any way the present invention yet.It will be recognized by those skilled in the art in the situation that not surmounting the spirit or scope of the present invention and can make conventional variation and amendment to following examples.Below prepare in the example of compositions, if not otherwise indicated, for example, with the amount preparation of 10,000 unit formulations that feed intake (tablet).Below prepare in the example of compositions, if not otherwise indicated, various materials are all pulverized before use and can be passed through 80 mesh sieve.
Surface tension test method: the surface tension feature of the various tablets of the present invention (or solid composite medicament of other form) is measured according to this method; Get test sample appropriate, add distilled water and dissolve and dilute the solution that to make containing the concentration of iodine (I) be 1mg/ml, full-automatic surface tension instrument/the interfacial tensimeter of JYW-200B micro-control for this solution (Chengde gold and instrument manufacturing company limited produce) is measured its surface tension, and result is taking dyn/cm as unit representation.
a, preparation example part
Some have been prepared and have had the solid composite medicament of feature of the present invention in this part.
preparation example 1: the preparation of cydiodine tablet
Formula (in every amount)
Cydiodine: be 5mg containing available iodine (I),
Lactose: 50mg.
Preparation method: cydiodine is fully mixed with lactose; This mixed-powder material is flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in and within 18 hours, (under room temperature, dispose with the seal box sealing disposal of 75% ethanol saturated air atmosphere; When not specified in the present invention, be all like this); Then the tablet that this powder material is squeezed on extruder to bulk (uses suitable large stretch of tablet machine, making thickness can be at 0.5～2cm, diameter can be the sheet of 2～5cm, this is a kind of dry granulation method of routine), again gained tablet is broken into granule (crossing 18 mesh sieves), 40～50 DEG C dry, (this tablet detects according to gas chromatography to be pressed into tablet, remaining ethanol do not detected), every contains the tablet that available iodine (I) is 5mg, aluminum-plastic composite membrane packs, and to obtain final product, and this sample is designated as Ex1.
Reference examples 11: with reference to above preparation example 1, different is only in the preparation when tablet, and mixed material direct pressing is become to every tablet of tablet that contains iodine (I) 5mg, and gained tablet is designated as D11 (direct powder compression).
Reference examples 12: with reference to above preparation example 1, different is only that preparation method changes the wet granule compression tablet technique that uses following routine into: cydiodine is fully mixed with lactose; Be that wetting agent carries out wet granulation by this mixed-powder material with 75% ethanol, wet granular is dry at 40～50 DEG C, (this tablet detects according to gas chromatography to be pressed into tablet again, remaining ethanol do not detected), every contains the tablet that available iodine (I) is 5mg, aluminum-plastic composite membrane packs, and gained tablet is designated as D12 (wet granule compression tablet method).
Reference examples 13: with reference to formula and the method for making of above preparation example 1, different is only uses the povidone iodine described in 2005 editions two the 823rd page of Chinese Pharmacopoeia to replace preparation example cydiodine used (every is 5mg containing available iodine (I)) cydiodine, and gained tablet is designated as D13.
Reference examples 14: use the formula of reference examples 13, but its method for making carry out according to the method for making of reference examples 12, gained tablet is designated as D14.
preparation example 2: the preparation of cydiodine tablet
Formula (in every amount)
Cydiodine: be 5mg containing available iodine (I),
Mannitol: 50mg.
Preparation method: cydiodine is fully mixed with mannitol; This mixed-powder material is flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in and within 15 hours, (under room temperature, dispose with the seal box sealing disposal of 80% ethanol saturated air atmosphere; When not specified in the present invention, be all like this); Then the tablet that this powder material is squeezed on extruder to bulk (uses suitable large stretch of tablet machine, making thickness can be at 0.5～2cm, diameter can be the sheet of 2～5cm, this is a kind of dry granulation method of routine), again gained tablet is broken into granule (crossing 18 mesh sieves), 40～50 DEG C dry, (this tablet detects according to gas chromatography to be pressed into tablet, remaining ethanol do not detected), every contains the tablet that available iodine (I) is 5mg, aluminum-plastic composite membrane packs, and to obtain final product, and this sample is designated as Ex2.
Reference examples 21: with reference to above preparation example 2, different is only in the preparation when tablet, and mixed material direct pressing is become to every tablet of tablet that contains iodine (I) 5mg, and gained tablet is designated as D21 (direct powder compression).
Reference examples 22: with reference to above preparation example 2, different is only that preparation method changes the wet granule compression tablet technique that uses following routine into: cydiodine is fully mixed with mannitol; Be that wetting agent carries out wet granulation by this mixed-powder material with 80% ethanol, wet granular is dry at 40～50 DEG C, (this tablet detects according to gas chromatography to be pressed into tablet again, remaining ethanol do not detected), every contains the tablet that available iodine (I) is 5mg, aluminum-plastic composite membrane packs, and gained tablet is designated as D22 (wet granule compression tablet method).
Reference examples 23: with reference to formula and the method for making of above preparation example 2, different is only uses the povidone iodine described in 2005 editions two the 823rd page of Chinese Pharmacopoeia to replace preparation example cydiodine used (every is 5mg containing available iodine (I)) cydiodine, and gained tablet is designated as D23.
Reference examples 24: use the formula of reference examples 23, but its method for making carry out according to the method for making of reference examples 22, gained tablet is designated as D24.
In addition, provide separately cydiodine raw material, povidone iodine raw material, lactose, mannitol, for measuring their surface tension feature.Wherein lactose and mannitol are in the time being mixed with aqueous solution, and its concentration is equivalent to the mensuration concentration of preparation example 1 tablet in water, is 10mg/ml.
The surface tension of measuring above Ex1, D11～D14, the each tablet of Ex2, D21～D24 and cydiodine raw material, povidone iodine raw material, lactose, mannitol according to surface tension test method, result is respectively as following table 1.
Table 1:
| Ex1： | 57.3dyn/cm； | Ex2： | 65.7dyn/cm； |
| D11： | 85.3dyn/cm； | D21： | 87.7dyn/cm； |
| D12： | 88.7dyn/cm； | D22： | 84.4dyn/cm； |
| D13： | 86.5dyn/cm； | D23： | 88.5dyn/cm； |
| D14： | 85.1dyn/cm； | D24： | 85.6dyn/cm； |
| Cydiodine: | 91.3dyn/cm； | Lactose: | 63.7dyn/cm； |
| Povidone iodine: | 96.8dyn/cm； | Mannitol: | 60.6dyn/cm |
From the above results, the combination of cydiodine and lactose or mannitol, and while adopting the inventive method to prepare, can greatly reduce the surface tension of compositions, but without the inventive method processing, or be all the povidone iodine of Operand, but do not present this variation tendency.
In addition, respectively with reference to formula and the method for making of preparation example 1, different is only that lactose is wherein replaced with to glucose, sorbitol, fructose, sodium chloride, sucrose, the tablet preparing after measured, the surface tension of their aqueous solution is all within the scope of 80～88dyn/cm, although show all have the surface tension that can not effectively reduce its aqueous solution with similar deliquescent these the conventional adjuvants of lactose.
preparation example 3: the preparation of cydiodine tablet
Formula (in every amount)
Cydiodine: be 5mg containing available iodine (I),
Lactose: 30mg.
Preparation method: cydiodine is fully mixed with lactose; This mixed-powder material is flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in the seal box sealing disposal of 90% ethanol saturated air atmosphere 12 hours; Then be prepared into tablet according to the method for preparation example 1, this sample is designated as Ex3.The surface tension of this sheet agent solution is 61.3dyn/cm.
preparation example 4: the preparation of cydiodine tablet
Formula (in every amount)
Cydiodine: be 5mg containing available iodine (I),
Lactose: 100mg.
Cydiodine used according to the cydiodine making under " preparation of (one) cydiodine " item in CN1028485C embodiment mono-, comprises 173mg available iodine (I) with HP-β-CD in every gram of material of this cydiodine.
Preparation method: cydiodine is fully mixed with lactose; This mixed-powder material is flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in the seal box sealing disposal of 90% ethanol saturated air atmosphere 24 hours; Then be prepared into tablet according to the method for preparation example 1, this sample is designated as Ex4.The surface tension of this sheet agent solution is 43.2dyn/cm.
preparation example 5: the preparation of cydiodine tablet
Formula (in every amount)
Cydiodine: be 5mg containing available iodine (I),
Mannitol: 80mg.
Cydiodine used according to the cydiodine making under " preparation of (one) cydiodine " item in CN1028485C embodiment mono-, comprises 155mg available iodine (I) with gamma-cyclodextrin in every gram of material of this cydiodine.
Preparation method: cydiodine is fully mixed with mannitol; This mixed-powder material is flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in the seal box sealing disposal of 60% ethanol saturated air atmosphere 12 hours; Then be prepared into tablet according to the method for preparation example 1, this sample is designated as Ex5.The surface tension of this sheet agent solution is 67.6dyn/cm.
preparation example 6: the preparation of cydiodine tablet
Formula (in every amount)
Cydiodine: be 5mg containing available iodine (I),
Mannitol: 75mg.
Cydiodine used according to the cydiodine making under " preparation of (one) cydiodine " item in CN1028485C embodiment mono-, comprises 147mg available iodine (I) with alpha-cyclodextrin in every gram of material of this cydiodine.
Preparation method: cydiodine is fully mixed with mannitol; This mixed-powder material is flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in the seal box sealing disposal of 80% ethanol saturated air atmosphere 15 hours; Then be prepared into tablet according to the method for preparation example 1, this sample is designated as Ex6.The surface tension of this sheet agent solution is 58.2dyn/cm.
In addition, the formula of above preparation example 3, preparation example 4, preparation example 5, preparation example 6, prepares tablet according to reference examples 11, reference examples 12 methods respectively, and the surface tension of the solution of 8 kinds of tablets of gained is all within the scope of 81～88dyn/cm.
preparation example 7: the preparation of cydiodine tablet
Formula (in every amount)
Preparation method: cydiodine is fully mixed with lactose, carboxymethyl starch sodium (having the effect of disintegrating agent), PVP-K30 (as dry adhesives), this mixed-powder material is flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in the seal box sealing disposal of 75% ethanol saturated air atmosphere 18 hours, then the tablet that this powder material is squeezed on extruder to bulk (uses suitable large stretch of tablet machine, making thickness can be at 0.5～2cm, diameter can be the sheet of 2～5cm, this is a kind of dry granulation method of routine), again gained tablet is broken into granule (crossing 18 mesh sieves), 40～50 DEG C dry, mix homogeneously with PEG6000 (as lubricant) again, (this tablet detects according to gas chromatography to be pressed into tablet, remaining ethanol do not detected), every contains the tablet that available iodine (I) is 5mg, aluminum-plastic composite membrane packs, obtain, this sample is designated as Ex8.The surface tension of this sheet agent solution is 59.3dyn/cm.
b, test portion
test example 1: extracorporeal disinfecting effect
According to 1 " Cydiodine buccal tablet fungicidal effectiveness " contained method of CN1028485C (China Patent No. ZL90106682.6) description 3 hurdle embodiment bis-, with Ex1 tablet, D11～D14 tablet, Ex2 tablet, D21～D24 tablet, Ex3～Ex7 tablet, cydiodine raw material, povidone iodine raw material is reagent, test these reagents (amount of iodine is 10ppm) to beta hemolytic streptococcus, do not understand sugared bacteroid, peptostreptococcus anaerobius, the killing rate (%) of actinomyces pseudonecrophorus in the time of 2min and 10min, result shows, all samples to four kinds of antibacterials the killing rate when the 2min all lower than 75%, but during to 10min, killing rate all reaches 100%, and various sample to same antibacterial to kill situation basic identical.
Above result shows, these different samples there is no difference to the killing effect of external indivedual oral cavities common pathogen.
test example 2: In Vitro Bacteriostasis effect
According to the document (Shao Qixiang of Shao Qixiang etc., Deng, the pharmacodynamic study of ofloxacin ear drops, Zhenjiang medical college journal, 1996, 6 (3): 215) about " detection method of 1.2.3MIC ", with Ex1 tablet, D11～D14 tablet, Ex3～Ex7 tablet, cydiodine raw material, povidone iodine raw material is reagent, test the In Vitro Bacteriostasis effect of following a few strain typical cases that the clinical separation of these reagents obtains and otitis media common pathogen (with MIC50, ug/ml, represent): staphylococcus aureus, Staphylococcus albus, Staphylococcus citreus, Pseudomonas aeruginosa, escherichia coli, Salmonella typhi, alpha streptococcus, group B streptococcus, Diplococcus pneumoniae, Bacillus proteus, klebsiella, aerobacteria, bacillus pyocyaneus.
Result, for each strain antibacterial, MIC50 (the ug/ml of different reagents, all in available iodine I) be same magnitude, for example 12 kinds of materials are 6.25ug/ml to the MIC50 value of staphylococcus aureus, 12 kinds of materials are 2.5ug/ml to the MIC50 value of escherichia coli, and 12 kinds of materials are 0.4ug/ml to the staphylococcic MIC50 value of white.Show that various sample (although they form, have identical or different surface tension feature by identical or different material) has essentially identical In Vitro Bacteriostasis effect.
test example 3: to drug effect in the body of Cavia porcellus acute suppurative otitis media
According to document (the ancestor jasmine of Zong Li etc., Deng, the pharmacodynamic study of Effects of Ofloxacin Otic Solution, modern Application pharmacy, 1995, 12 (4): 28) about " therapeutic tests of 2 pairs of Cavia porcellus suppurative otitis medias " institute support method, with Ex1 tablet, D11～D14 tablet, Ex2 tablet, D21～D22 tablet, Ex3～Ex7 tablet, cydiodine raw material, totally 15 samples of povidone iodine raw material is reagent, dissolve and dilute before use the solution of making containing available iodine 1mg/ml with distilled water, for dripping ear, treating otitis media effect to caused by Staphylococcus aureus is investigated.The number of animals of each reagent group is 10, and using distilled water as blank.
Result shows:
(1) after treatment in 7 days, observe finding: Ex1 tablet, Ex2 tablet, seven groups of inflammatory reactions of Ex3～Ex7 tablet are all clearly better or fully recover, ear is dry, substantially without secretions; Blank group situation is with before treating; But unexpectedly, D11～D14 tablet, D21～D22 tablet, cydiodine raw material, eight groups of inflammatory reactions of povidone iodine raw material are showed no improvement, and in ear all has pussy discharge;
(2) Detection of pathogenic bacteria situation: each treated animal all animals before administration all detects antibacterial and is positive; Blank group all animals after administration 3 days and treatment in 7 days all detects antibacterial and is positive; Seven groups, Ex1 tablet, Ex2 tablet, Ex3～Ex7 tablet, after administration treatment in 3 days, each group all has 6～9 animals not detect antibacterial; Seven groups, Ex1 tablet, Ex2 tablet, Ex3～Ex7 tablet, after administration treatment in 7 days, each group all animals does not all detect antibacterial, detects result and is all negative; Eight groups, D11～D14 tablet, D21～D22 tablet, cydiodine raw material, povidone iodine raw material, after administration treatment in 3 days, each group all has 1～3 animal not detect antibacterial; Eight groups, D11～D14 tablet, D21～D22 tablet, cydiodine raw material, povidone iodine raw material, after administration treatment in 7 days, each group all has 2～4 animals not detect antibacterial;
(3) number of animals that for example, Ex1 tablet group does not detect antibacterial after administration 3 days and treatment in 7 days is respectively 8 and 10; The number of animals that D11 tablet group does not detect antibacterial after administration 3 days and treatment in 7 days is respectively 2 and 3; The number of animals that D12 tablet group does not detect antibacterial after administration 3 days and treatment in 7 days is respectively 2 and 4.Visible, the tablet with feature of the present invention has drug effect in significantly more excellent body, although their material composition is identical and in vitro effects is identical.
test example 4: to drug effect in the body of Cavia porcellus acute suppurative otitis media
With reference to the method for test example 3, different is only the document (Weiqiang with reference to Weiqiang etc. in the time building animal model, Deng, the pharmacodynamics of pipemidic acid drop pill treatment suppurative otitis media, Journal of Chinese Hospital Pharmacy, 2003,23 (2): 102) such, every animal inoculation 0.1mL mixed bacteria liquid, it consists of: 5% gastric Mucin, staphylococcus aureus 0.4 × 10
7, group B streptococcus 1 × 10
6, Pseudomonas aeruginosa 1.6 × 10
7, Bacillus proteus 1.6 × 10
7.
Result shows:
(1) after treatment in 7 days, observe finding: Ex1 tablet, Ex2 tablet, seven groups of inflammatory reactions of Ex3～Ex7 tablet are all clearly better or fully recover, ear is dry, substantially without secretions; Blank group situation is with before treating; But unexpectedly, D11～D14 tablet, D21～D22 tablet, cydiodine raw material, eight groups of inflammatory reactions of povidone iodine raw material are showed no improvement, and in ear all has pussy discharge;
(2) Detection of pathogenic bacteria situation: each treated animal all animals before administration all detects antibacterial and is positive; Blank group all animals after administration 3 days and treatment in 7 days all detects antibacterial and is positive; Seven groups, Ex1 tablet, Ex2 tablet, Ex3～Ex7 tablet, after administration treatment in 3 days, each group all has 6～8 animals not detect antibacterial; Seven groups, Ex1 tablet, Ex2 tablet, Ex3～Ex7 tablet, after administration treatment in 7 days, each group all animals does not all detect antibacterial, detects result and is all negative; Eight groups, D11～D14 tablet, D21～D22 tablet, cydiodine raw material, povidone iodine raw material, after administration treatment in 3 days, each group all has 1～3 animal not detect antibacterial; Eight groups, D11～D14 tablet, D21～D22 tablet, cydiodine raw material, povidone iodine raw material, after administration treatment in 7 days, each group all has 2～4 animals not detect antibacterial;
(3) number of animals that for example, Ex1 tablet group does not detect antibacterial after administration 3 days and treatment in 7 days is respectively 7 and 10; The number of animals that D11 tablet group does not detect antibacterial after administration 3 days and treatment in 7 days is respectively 1 and 2; The number of animals that D12 tablet group does not detect antibacterial after administration 3 days and treatment in 7 days is respectively 2 and 3.Visible, the tablet with feature of the present invention has drug effect in significantly more excellent body, although their material composition is identical and in vitro effects is identical.
test example 5: to drug effect in the body of White Rabbit acute suppurative otitis media
Get 20 of White Rabbits, in every side tympanum of every White Rabbit, inject 0.1mL mixed bacteria liquid, it consists of: 5% gastric Mucin, staphylococcus aureus 0.4 × 10
8, group B streptococcus 1 × 10
7, Pseudomonas aeruginosa 1.6 × 10
8, Bacillus proteus 1.6 × 10
8, gonococcus 1 × 10
7.
After 7 days, get White Rabbit auditory meatus liquid (being basal part of the ear secretions) and do antibacterial culturing inspection, the infection model White Rabbit of positive bacteria cultivation results (at least should have 3 kinds of antibacterial culturing positive) is divided into test group (Ex1 tablet, D11 tablet, D12 tablet) and matched group at random, every group 5, each 10 ears, test group tablet dissolves and dilutes the solution of making containing available iodine 2mg/ml with distilled water; Each 1～2 (noting not dropping in ear outer), every day 5 times, successive administration 7 days, within the 2nd day after drug withdrawal, getting White Rabbit auditory meatus liquid (being basal part of the ear secretions) is coated with and tests and antibacterial culturing, the negative pathogen that is judged to be of cultivation results is turned out cloudy, and calculates the pathogen negative conversion rate of every group with following formula.
Pathogen positive ear number × 100% of pathogen before ear number/medication of turning out cloudy after pathogen negative conversion rate=medication
Result: matched group pathogen negative conversion rate is 0; Ex1 tablet group pathogen negative conversion rate is 100%; D11 tablet group, D12 tablet group pathogen negative conversion rate are respectively 40% and 30%.
medicine box example
Get one of seven kinds of tablets of Ex1～Ex7 tablet 1, use plastic-aluminum combined film phonograph seal, be placed in medicine packing box, in this medicine box, use the solution of 1 bottle of 5ml of [Dan bottle subpackage, this solution is one of water, 0.02M sodium hydrogen phosphate buffer (phosphoric acid is adjusted pH7.0), 0.025M sodium citrate buffer (citric acid is adjusted pH7.0), 0.02M sodium-acetate buffer (acetic acid is adjusted pH6.8) four again.In this medicine box, also comprise medication instruction, record is placed in tablet before use after solution dissolves and re-uses in dripping an ear.
Claims (10)
1. a solid composite medicament of using for dripping ear, it comprises cydiodine, diluent.
2. according to the solid composite medicament of claim 1, wherein said diluent is water-soluble diluent; Or wherein said diluent is water-soluble diluent, is selected from: glucose, mannitol, sorbitol, lactose, fructose, sodium chloride, sucrose etc. and their combination; Or described water-soluble diluent is selected from: lactose, mannitol with and combination.
3. according to the solid composite medicament of claim 1, the amount that wherein comprises cydiodine is counted 5 weight portions with iodine (I), the amount of diluent is 20～200 weight portions (amount of for example diluent is 25～150 weight portions, for example, be 30～100 weight portions); Or, it is during with water dissolution the dilution solution that to make containing the concentration of iodine (I) be 1mg/ml, this solution has the surface tension of 20～100dyn/cm, or this solution has the surface tension of 30～80dyn/cm, or this solution has the surface tension of 40～70dyn/cm.
4. according to the solid composite medicament of claim 1, it is the form that is tablet, granule or capsule; For example it is the form that is tablet; For example it is the form that is tablet, this tablet is to prepare in the following manner substantially: make the uniform material of cydiodine and mixing diluents flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in and dispose 12～24 hours with the seal box sealing of ethanol saturated air atmosphere; Then this powder material is squeezed into the tablet of bulk, then gained tablet is broken into granule, dry, be pressed into tablet; Or it is the form that is tablet, it optionally also comprises optional disintegrating agent, optional binding agent and/or optional lubricant.
Described in claim 1 to 4 any one solid composite medicament in the purposes for the preparation of prevention and treatment ear diseases associated with inflammation.
6. according to the purposes of claim 5, wherein said ear diseases associated with inflammation is to betide the diseases associated with inflammation that middle ear, internal ear etc. are located; For example, wherein said ear diseases associated with inflammation is otitis media; For example, wherein said otitis media comprises non-suppurative otitis media and suppurative otitis media; For example, wherein said suppurative otitis media comprises acute suppurative otitis media and chronic suppurative otitis media; For example, wherein said ear diseases associated with inflammation is to infect by antibacterial the inflammatory diseases causing.
7. according to the purposes of claim 6, wherein said antibacterial infects and refers to that being selected from following antibacterial infects: staphylococcus aureus, Staphylococcus albus, Staphylococcus citreus, Pseudomonas aeruginosa, escherichia coli, Salmonella typhi, Salmonella paratyphi B, alpha streptococcus, group B streptococcus, Diplococcus pneumoniae, Shigella dysenteriae, Bacillus proteus, klebsiella, aerobacteria, enterobacter agglomerans, enterobacter cloacae, bacillus subtilis.
8. a medicine box product, it comprises packing box, is wrapped in solid composite medicament in this packing box and for dissolving the solvent of this solid composite medicament; For example,, as described in wherein said solid composite medicament embodiment as arbitrary in first aspect present invention.
9. medicine box product according to Claim 8, wherein said solvent is selected from: water, phosphate buffer, citrate buffer, borate buffer solution, acetate buffer etc.; Further, the amount of wherein said solvent is that, while making described solid composite medicament be dissolved in wherein, iodine (I) concentration in solution reaches the scope of 0.2～5mg/ml, for example reach the scope of 0.5～2.5mg/ml, for example, reach the scope of 0.5～2mg/ml; Further, wherein also comprise the operation instructions of this medicine box product; Further, in described operation instructions, recorded to use before this medicine box product described solid composite medicament has been joined to the operating procedure of dissolving in described solvent.
10. prepare the particularly method of tablet of solid composite medicament described in claim 1 to 4 any one, it consists essentially of following steps: make the uniform material of cydiodine and mixing diluents flat auxiliary on stainless steel flat plate to be no more than the thickness of one centimetre, then be placed in and dispose 12～24 hours with the seal box sealing of ethanol saturated air atmosphere; Then this powder material is squeezed into the tablet of bulk, then gained tablet is broken into granule, dry, be pressed into tablet; Further, as described in wherein said solid composite medicament embodiment as arbitrary in first aspect present invention.
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